LuPARP: Phase 1 trial of 177Lu-PSMA-617 and olaparib in patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Shahneen Sandhu, Anthony M. Joshua, Louise Emmett, Megan Crumbaker, Mathias Bressel, Rhonda Huynh, Patricia Diana Banks, Roslyn Wallace, Anis Hamid, Andrisha Jade Inderjeeth, Ben Tran, Arun Azad, Ramin Alipour, Grace Kong, Aravind Ravi Kumar, Javad Saghebi, Scott Williams, Timothy J. Akhurst, Rodney J. Hicks, Michael S Hofman
Journal: Journal of Clinical Oncology (2023)

5005 Background: 177 Lu-PSMA-617, a PSMA-directed, radionuclide therapy improves progression free survival (PFS) and overall survival (OS) in patients (pts) with mCRPC. Although many pts benefit from treatment, approximately a third have primary resistance, median PFS is 5.1 months and all pts inevitably relapse. Poly (ADP-ribose) polymerase (PARP) is implicated in repairing radiation-induced DNA single-strand breaks (SSBs). The potent PARP inhibitor (PARPi) olaparib results in the conversion of DNA SSBs to lethal double-strand breaks. Multiple preclinical studies have shown enhanced anti-tumor activity from combined PARPi and radiotherapy. LuPARP aims to evaluate the safety and efficacy of the combination of 177 Lu-PSMA-617 and olaparib. Methods: 48 pts with mCRPC and high PSMA expression (SUVmax 15 at a site of disease, and SUVmax ≥ 10 at other measurable sites) without discordant FDG positive/PSMA negative disease will be enrolled in two stages: dose-escalation (standard 3+3 design) and dose-expansion at the recommended phase 2 dose (RP2D). 177 Lu-PSMA-617 is administered at 7.4 GBq IV on day 1, every 6 weeks for up to 6 cycles in conjunction with 9 prespecified dose schedules of olaparib. The dose-limiting toxicity (DLT) period is 6 weeks. The primary objectives are establishing the DLTs and RP2D. Secondary objectives are toxicity, radiological PFS (rPFS), PSA response rate (PSA50-RR), PSA-PFS, objective response rate (ORR) and OS. Responses are assessed by 3-weekly PSA and conventional and PSMA PET/CT imaging every 12 weeks. Results: 29 pts (median age 70 years: range: 52-84; prior docetaxel: 97%; prior androgen receptor pathway inhibitor: 100%) received 177 Lu-PSMA-617 on day 1 with escalating doses of olaparib (cohorts 1-6: 50mg - 300 mg BD days 2-15) or alternate olaparib schedules (cohort 7: 200 BD days - 4 to 14; cohort 8: 300 BD days - 4 to 14; cohort 9: 300 mg BD days -4 to 18) for up to 6 cycles. No DLTs were reported. Common treatment related adverse events (TRAE) (≥10%) were Grade (G) 1-2 and included xerostomia (83%), nausea (62%), fatigue (34%), constipation (31%), anorexia (17%), vomiting (14%) and diarrhea (10%). Hematologic TRAE included anemia (G1: 14%; G2: 7%; G3: 7%), thrombocytopenia (G1: 14%; G2: 7%; G3: 3%) and neutropenia (G1: 3%; G3: 7%) that were transient and without clinical sequelae. Across cohorts 1-9, the PSA50-RR was 62% (18/29) and PSA90-RR was 48% (14/29). Five of the 7 pts (71%) with RECIST measurable disease had a partial response. Conclusions: The combination of 177 Lu-PSMA-617 and olaparib is well tolerated and has promising activity. Three further patients are being enrolled to cohort 9 to confirm the RP2D ahead of dose-expansion. Clinical trial information: NCT03874884 . [Table: see text]